Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women. There are few treatment options. See Kyan J. Allandadi et al., “Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges,” Cardiovasc Hematol Agents Med Chem. 2009 October; 7(4): 260-269. FSD can be classified under many subtypes. For example, female sexual arousal disorder (FSAD) is a disorder characterized by a persistent inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity. Female Sexual Interest/Arousal Disorder (FSIAD) is a diagnosis found when a subject experiences a lack of or significantly reduced sexual interest or arousal. Female hypoactive sexual desire disorder (FHSDD) is a general loss of interest in sexual activity. Other subtypes exist, for example, anorgasmia, a difficulty achieving orgasm. Currently, off-label use of testosterone has been prescribed. A therapy approved by the FDA in August 2015 is the Sprout Pharmaceuticals, Inc. product Addyi™ (flibanserin 100 mg), a once-daily, non-hormonal pill for the treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. In addition, there are several drugs that were the subject of clinical trials that affect signaling in the brain. See Wright, J. J., O'Connor, K. M. (2015), “Female sexual dysfunction,” Medical Clinics of North America, 99(3), 607-628. Because both hormonal and psycho-affective drugs can be associated with serious negative side effects, alternative treatment options would be desired for treating this prevalent condition.
The arousal phase of the female sexual response cycle involves genital mechanisms, such as clitoral, labial, and vaginal engorgement, as well as non-genital peripheral mechanisms, such as increases in body secretions, cutaneous vasodilation, and nipple erection. Nipple erection occurs via activation of adrenergic nerves. Smooth muscles in the nipple areola complex are contracted, thereby erecting the nipple. The role of nipple stimulation in influencing sexual desire and arousal in women prior to and during intercourse has been reported in the literature. Eighty-two percent of surveyed women report that stimulation of their nipples caused or enhanced their sexual arousal. See Levin, R., Meston, C. (2006), “Nipple/Breast stimulation and sexual arousal in young men and women,” Journal of Sexual Medicine, 3(3), 450-454; Levin, R. (2006), “The breast/nipple/areola complex and human sexuality,” Sexual and Relationship Therapy, 21(2), 237-249. In addition, stimulation of a women's nipple has been shown to correlate with increased oxytocin levels in blood serum. See Stein, J. L., Bardeguez, A. D., Verma, U. L., Tegani, N. (1990), “Nipple stimulation for labor augmentation,” Journal of Reproductive Medicine, 35(7), 710-714. Oxytocin is a peptide hormone shown to play a role in sexual satisfaction and desire.
U.S. Pat. No. 4,853,216 (Koslo et al.) reports topical application of alpha-1 adrenergic receptor agonists (“A1AR agonists”) to a hair-bearing skin area to facilitate the physical or chemical handling of the hair. The purpose is to activate the pilomotor effect and erect the hair on the skin. This may be applied as a pretreatment prior to shaving or incorporated into a shaving composition, such as shaving cream. U.S. Pat. No. 4,853,216 discloses that suitable A1AR agonists include phenylephrine and methoxamine. See U.S. Pat. No. 4,853,216 at col. 2 lines 46-48. WO2004041259 (Thurlow et al.) describes the use of alpha 1 adrenergic receptor antagonists for the treatment of FSD. The reference does not describe application of the antagonist to at least a portion of the nipple-areola complex, and focuses rather on inhibitors of receptors in the vaginal tissue. It is unexpected from this teaching that an A1AR agonist would be useful for treatment of FSD when applied to at least a portion of the nipple-areola complex.
A1AR agonists bind to α1-receptors on vascular smooth muscle and induce smooth muscle cell contraction, thus mimicking the effects of sympathetic neurons activation of smooth muscles via adrenergic receptors. Phenylephrine is a selective A1AR agonist. Phenylephrine is used as a decongestant, for which it is sold as an oral medicine or a nasal spray. Phenylephrine is also sold as a topical ointment to prevent or reduce symptoms of hemorrhoids. Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. US Patent Application Pub. 2004/0198706 (Carrara et al.) discloses formulations for providing transdermal or transmucosal delivery of active agents. The formulations treat symptoms of hormonal disorders including female sexual desire disorder. The active agents may be selected from a large group of therapeutic agents, one of which is phenylephrine. The reference does not describe application of the transdermal or transmucal dosage forms to the nipple-areola complex. It is unexpected from this teaching that an A1AR agonist such a phenylephrine would be useful for treatment of FSD when applied to the nipple-areola complex.